Age-related macular degeneration(AMD) and RANIBIZUMAB (Lucentis)

Aggiornamento biotecnologico:

MoAb anti VEGF

Giulia Germena

AMD

• DRY (non-neovascular)• Atrophic cell death in the

macula• No leakage

• WET (neovascular)• Abnormal neovascularization

under the macula• Leakage of blood or serum

Althought neovascular AMD affects only ~10% of patients with AMD,it is responsible of ~ 80% of cases among patiens with severe vision loss.

[4]

Overview

Strong risk factor:• Aging• Smoking• Family history of macular

degeneration• Macular Degeneration Gene

(Complement Factor H)

Other factor:• Sunlight exposure• Hypertension• Hight fat intake

Normal vision

AMD vision

Narayanan et al. Nature Reviews Drug Discovery 5, 815–816 (October 2006) [4]

NeovascularAMD involves the growth

of abnormal newblood vessels into the sub-

retinal space andretinal pigment epithelium.

These weak vesselsleak blood or serum,

causing damage to themacula, which is crucial for

fine vision.

Why the vision loss?

VEGF pathway and angiogenesis

Adapted from BioCarta Pathway [10]

Treatment of macular degenerationsiRNA VEGF

siRNA VEGFR-1

MoAb anti

VEGF

aptamer anti

VEGF

Inhibits integrin expression

Inhibits angiogenesis downstream pathway

Gene therapy

PEDF=anti-angiogenic

[8]

Treatment of macular degeneration

Laser:• Thermal photocoagulation• Photodynamic therapy (PDT): intravenously injection of verteporfin

(Visudyne) and laser activation.• Slows retinal damage

• NO stop of the vision loss

• NO restore of the vision

Injected inside the the eye (intravitreous injection):• Macugen (Pegaptanib) Treatment • Lucentis (Ranibizumab) Treatment

Macugen (Pegaptanib) Treatment

Macugen is a selective PEG-conjugated aptamer that blocks VEGF actions and prevents the growth of abnormal new vessels and prevents leakage of fluid and blood in the retina.

Approved by the FDA in December 2004.

Recommended dose: 0.3 mg for i.i. administered once every 6 weeks.

[8]

Steinbrook, R. (2006). "The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration."

N Engl J Med 355(14): 1409-12 [1].

Ranibizumab (Lucentis)

Ranibizumab is a fragment of a recombinant monoclonal antibody that binds to and inhibits all the biologically

active forms of the VEGF-A. Is produced in E.coli and is

designed for intraocular use.

Bevacizumab is produced in CHO and is designed for

intravenous infusion.

Both the antibody are derived from the same mouse monoclonal antibody. However, ranibizumab has been genetically engineered to

increase its affinity for binding and inhibiting the growth factor.

The FDA approval of Lucentis (June 2006) is based on data from two large Phase III clinical trials (MARINA and ANCHOR).

In these studies:

Trials for ranibizumab:

• Nearly all patients (approximately 95 percent) treated with Lucentis (0.5 mg) maintained (defined as the loss of less than 15 letters in visual acuity) and up to 40 percent improved (defined as the gain of 15 letters or more in visual acuity) vision at one year, as measured on the Early Treatment of Diabetic Retinopathy (ETDRS) eye chart.

• On average, patients treated with Lucentis in the MARINA [2] study experienced an improvement from baseline of 6.6 letters at two years compared to a loss of 14.9 letters in the sham group. In the ANCHOR [7] study, patients treated with Lucentis, on average, experienced an 11.3 letter gain from baseline at one year compared to a loss of 9.5 letters in the (PDT) control group.

Minimally classic/occult trial of the Anti-VEGF antibody Ranibizumab In the treatment of Neovascular AMD

Adapted from [8]

MARINA Trial

Too expensive and so…..One Lucentis injection cost $ 1950; in the clinical trials that reported a

gain in vision, Lucentis was used every month.

12 injection per year will cost $ 23,400.

Chance:

•NO vision gain

•Use something less expensive

[8]

The off-label use of AvastinFebruary 2004, the FDA approved bevacizumab for the treatment of

metastatic cancer of the colon or rectum; a 4ml vial (100mg of MoAb) cost $ 550. On the molar basis a dose of 0.05ml (1.25mg of MoAb) is similar

to the approved dose of ranibizumab. In 2005, Rosenfeld’s group published two case reports showing that the use of bevacizumab in AMD

patients gave benefits.[3]

PROS and CONS:

•Bevacizumab is 3 times large than ranibizumab and may remain in the eye longer frequency of injection decrease. Moreover have longer half-

life compared to ranibizumab.

•Ranibizumab have greater affinity for VEGF and is formulated for intraocular use so, more drugs may penetrate all the layer of the retina;

moreover have an half-life of hours that could theoretically be associated with less systemic toxicity; the lacking of the Fc portion could induce less

inflammation.

Market for therapies

• The worldwide pharmaceutical market for the treatment of neovascular AMD is currently defined by only 2 products: verteporfirin(Visudyne, Novartis) and pegaptanib(Macugen, OSI Pharmaceuticals/Pfizer). Ranibizumab is the first treatment that stabilize vision in more than 90% of wet AMD patiens and improve vision in a significant proportion of patients.

• Althought bevacizumab and ranibizumab are related, Genentech engineered ranibizumab specifical for penetrate the retina and there are no plans to develop bevacizumab for AMD.

• The National Eye Institute has received an outside proposal to conduct a comparative study, and results from such an investigation would have a significant impact on the commercial potential of ranibizumab.

[4]

References:

• [1] Steinbrook, R. (2006). "The price of sight--ranibizumab, bevacizumab, and the treatment of macular degeneration." N Engl J Med 355(14): 1409-12.

• [2] Rosenfeld, P. J., D. M. Brown, et al. (2006). "Ranibizumab for neovascular age-related macular degeneration." N Engl J Med 355(14): 1419-31.

• [3] Rosenfeld, P. J. (2006). "Intravitreal avastin: the low cost alternative to lucentis?" Am J Ophthalmol 142(1): 141-3.

• [4] Narayanan, R., B. D. Kuppermann, et al. (2006). "Ranibizumab." Nat Rev Drug Discov 5(10): 815-6.

• [5] Ferrara, N. (2002). "VEGF and the quest for tumour angiogenesis factors." Nat Rev Cancer 2(10): 795-803.

• [6] Dass, C. R., T. M. Tran, et al. (2007). "Angiogenesis inhibitors and the need for anti-angiogenic therapeutics." J Dent Res 86(10): 927-36.

• [7] Brown, D. M., P. K. Kaiser, et al. (2006). "Ranibizumab versus verteporfin for neovascular age-related macular degeneration." N Engl J Med 355(14): 1432-44.

• [8] http://www.agingeye.net/• [9] http://www.gene.com• [10] http://www.biocarta.com